Buspirone, chemically: 8-4-4-2-pyrimidinyl)-piperazinyl[butyl]-8-azaspiro(4,5)-decane-7, 9-dione is a pharmaceutically active compound disclosed in U.S. Pat. No. 3,717,634. This compound has been found to be effective for the treatment of anxiety disorders including depression.
Buspirone suffers from the drawback of a very high first pass metabolism. Only about 4% of a therapeutic dose will ordinarily reach the systemic circulation unchanged after oral administration (Mayol et al., Clin. Pharmacol. Ther., 37, 210, 1985).
Buspirone also exhibits great intra- and inter-individual variations in absorption. This variability has been demonstrated by up to 10-fold differences in the maximum plasma concentrations resultant from a given dose of this drug (Gammans et al., American J. Med., 80, Suppl. 3B, 41-51, 1986).
Several metabolites of buspirone have been identified, including several hydroxylated derivatives that show little pharmacological activity. The major metabolite, 1-(2-pyrimidinyl piperazine (1-PP), has been found to be about 20-25% as potent an anxiolytic agent as buspirone in pharmacologic testing.
The biological half-life of buspirone is very short and variable in man, on an order of 2-11 hours. The much less active metabolite, 1-PP, exhibits much slower elimination (Mayol et al., Clin. Pharmacol. Ther., 37, 210 1985). These pharmacokinetic properties necessitate a rather frequent daily dosing regimen which would be expected to have a negative effect on patient compliance.
Since buspirone is rapidly absorbed after an oral dose, high peak plasma values normally occur shortly after drug administration. These peak values are associated with the occurrence of undesired or adverse events commonly observed during the first days of treatment. These adverse effects can also seriously impact patient compliance because they can result in deliberate disruption of the drug therapy.
Since its clinical introduction, buspirone has suffered from a perceived lack of immediate effect. Much of this perception may be attributable to patient failures in compliance. Patient monitoring has evidenced inappropriate dosing--either using buspirone as a night-time dose or taking it as necessary (prn)--instead of using it in the consistent manner in which it is ordinarily prescribed.
Wide variation and unpredictability in the delivery of buspirone have been reported in articles such as Metabolism and Disposition of Buspirone by Gammans et al, the American Journal of Medicine, Mar. 31, 1988, Vol. 80. These studies reflect that systemic availability and plasma levels of buspirone may differ by 1,000% or more, dependant on the individual and other factors.
Attempts to improve the oral delivery of buspirone have been only partially successful. U.S. Pat. No. 5,431,922 describes formulations of buspirone or a salt thereof imbedded in an inert matrix; formed into micro pellets; and in coated micro pellets to obtain an intermediate in vitro dissolution rate. This intermediate dissolution rate is said to permit less frequent dosing and reduced production of 1-(2-pyrimidinyl-2-piperazine (1-PP) metabolite. However, the comparative data in the examples of that patent continue to reflect wide variation in the buspirone plasma concentration levels, both over time and between patients.